1. Technical Field
The invention relates, in general, to esters of testosterone possessing androgenic activity and, in particular, to new long-acting cycloalkyl carboxylic acid esters of testosterone and pharmaceutical compositions thereof.
2. Background Information
The need for androgenic substances in the practice of medicine is well documented. Androgens may be used for the replacement of the natural hormone testosterone in hypogonadism and following castration. Androgens are commonly employed to accelerate growth in childhood, promote anabolism, stimulate erythropoiesis. Androgens are also employed as a palliative for recurrent and metastatic carcinoma of the breast. Both oral and parenteral formulations of androgens are currently available.
Cycloalkyl esters of testosterone have been described by van der Vies (U.S. Pat. No. 4,147,783) for use as orally administered androgens. The cycloalkyl group of the esters disclosed contains 7-12 carbons and is optionally substituted by aliphatic groups containing 1-6 carbon atoms.
A number of testosterone cycloalkylalkanoates have been described by Ott et al. (Journal of Clinical Endocrinology and Metabolism 12, 15 (1952)); one cycloalkyl carboxylic acid ester, testosterone 4-bicyclohexylcarboxylate, being mentioned. Ott et al evaluated the compounds disclosed therein for long-acting androgenic activity following a single subcutaneous injection of an oily solution (cottonseed oil) in rats. Testosterone 4-bicyclohexylcarboxylate was found to be less potent than the testosterone propionate standard. These investigators also studied an aqueous microcrystalline suspension of testosterone, but the results were "disappointing" and both the intensity and duration of action were less than the standard, testosterone propionate (see also U.S. Pat No. 2,566,358, Ott to The Upjohn Company for testosterone .beta.-cyclopentylopropionate).
Gould, et al. (Journal of the American Chemical Society 79, 4472 (1957)), disclosed a large number of testosterone esters including several substituted cyclohexanecarboxylates. Among the latter were the 2-, 3- and 4-methyl and 4-ethyl, propyl and isopropyl, and 3, 3, 5-trimethylcyclohexanecarboxylate. Most of these compounds exhibited a greater intensity, and all exhibited greater duration, of androgenic action than the standard employed, testosterone propionate. Unsubstituted testosterone cyclohexanecarboxylate and the corresponding 2-, 3-and 4-methyl substituted analogs were also administrated as aqueous suspensions and all were found to exhibit two to four times the duration of activity as that of the standard, testosterone propionate.
Weinbauer, et al. (Acta Endocrinologica (Copenh) 113, 128 (1986)), have reported the levels of testosterone and its metabolite, dihydrotestosterone, following a single intramuscular injection of an aqueous suspension of testosterone 17.beta.-(trans- 4-n-butyl)cyclohexanecarboxylate or testosterone enanthate standard in sesame oil in orchidectomized cynomolgus monkeys. Both intensity and duration of elevated hormone levels were greater following administration of testosterone 17.beta.-(trans-4-n-butyl) cyclohexanecarboxylate.
Thus, while oral and parenteral formulations of androgens are available, oral preparations require continual, daily self-medication and parenteral forms must be administered frequently to maintain physiological blood level. Compounds resulting from the esterification at position 17 of testosterone often exhibit enhanced duration of action following parenteral administration, however, many of the most potent of these drugs must be injected at weekly or biweekly intervals to maintain adequate therapeutic blood levels. In addition, many of these compounds produce high initial peak levels of testosterone which are in excess of normal physiological range.